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Syndromic Ear Anomalies and Renal Ultrasounds

Raymond Y. Wang, MD*; Dawn L. Earl, RN, CPNP‡; Robert O. Ruder, MD§; and
John M. Graham, Jr, MD, ScD‡

ABSTRACT. Objective. Although many pediatricians cific MCA syndromes that have high incidences of renal
pursue renal ultrasonography when patients are noted to anomalies. These include CHARGE association, Townes-
have external ear malformations, there is much confusion Brocks syndrome, branchio-oto-renal syndrome, Nager
over which specific ear malformations do and do not syndrome, Miller syndrome, and diabetic embryopathy.
require imaging. The objective of this study was to de- Patients with auricular anomalies should be assessed
lineate characteristics of a child with external ear malfor- carefully for accompanying dysmorphic features, includ-
mations that suggest a greater risk of renal anomalies. We ing facial asymmetry; colobomas of the lid, iris, and
highlight several multiple congenital anomaly (MCA) retina; choanal atresia; jaw hypoplasia; branchial cysts or
syndromes that should be considered in a patient who sinuses; cardiac murmurs; distal limb anomalies; and
has both ear and renal anomalies. imperforate or anteriorly placed anus. If any of these
Methods. Charts of patients who had ear anomalies features are present, then a renal ultrasound is useful not
and were seen for clinical genetics evaluations between only in discovering renal anomalies but also in the diag-
1981 and 2000 at Cedars-Sinai Medical Center in Los nosis and management of MCA syndromes themselves.
Angeles and Dartmouth-Hitchcock Medical Center in A renal ultrasound should be performed in patients with
New Hampshire were reviewed retrospectively. Only pa- isolated preauricular pits, cup ears, or any other ear
tients who underwent renal ultrasound were included in anomaly accompanied by 1 or more of the following:
the chart review. The literature was reviewed for the other malformations or dysmorphic features, a family
epidemiology of renal anomalies in the general popula- history of deafness, auricular and/or renal malforma-
tion and in MCA syndromes with external ear anomalies. tions, or a maternal history of gestational diabetes. In the
We defined a child as having an external ear anomaly absence of these findings, renal ultrasonography is not
when he or she had any of the following: preauricular indicated. Pediatrics 2001;108(2). URL: http://www.
pits and tags; microtia; anotia; or cup, lop, and other pediatrics.org/cgi/content/full/108/2/e32; external ear, re-
forms of dysplastic ears. A child was defined as having a nal, anomalies, ultrasound.
renal anomaly if an ultrasound revealed any of the fol-
lowing: unilateral or bilateral renal agenesis; hypoplasia;
crossed ectopia; horseshoe, pelvic, cystic kidney; hydro- ABBREVIATIONS. BOR, branchio-oto-renal; MCA, multiple con-
nephrosis; duplicated ureters; megaureter; or vesico- genital anomaly; TBS, Townes-Brocks Syndrome; OAVS, oculoau-
ureteric reflux. riculovertebral spectrum; M/A, microtia/anotia; IDM, infant of a
Results. Because clinical genetics assessments were diabetic mother; TCS, Treacher Collins syndrome.
made by the same clinician at both sites (J.M.G.), data
were combined. A total of 42 patients with ear anomalies

M
received renal ultrasound; 12 (29%) of them displayed any studies in the literature have noted a
renal anomalies. Of the 12 patients with renal anomalies, significant association between renal anom-
11 (92%) also received a diagnosis of MCA syndrome. alies and various ear anomalies. Ear pits
Eleven of 33 patients (33%) with MCA syndromes had and tags, perhaps the most common minor ear mal-
renal anomalies, whereas 1 of 9 patients (11%) with iso- formation, occur with a frequency of 5 to 6 per 1000
lated ear anomalies had renal anomalies. Specific disor- live births.1,2 In the pediatric population, structural
ders seen were CHARGE association, Townes-Brocks renal anomalies occur in 1 to 3 per 100 live births.3–5
syndrome, branchio-oto-renal syndrome, Nager syn-
Kohelet and Arbel6 noted that among 70 consecutive
drome, and diabetic embryopathy.
Conclusions. We conclude that ear malformations are children who had isolated preauricular tags and
associated with an increased frequency of clinically sig- were examined by renal ultrasonography, 6 (8.6%)
nificant structural renal anomalies compared with the had urinary tract abnormalities (5 with hydrone-
general population. This is due to the observation that phrosis, 1 with horseshoe kidney). In a separate
auricular malformations often are associated with spe- study, among 69 children who had preauricular si-
nuses and were examined by renal ultrasound, 3
From the *University of California–Los Angeles, School of Medicine; ‡De- (4.3%) demonstrated renal anomalies (2 with hydro-
partment of Medical Genetics, Ahmanson Department of Pediatrics, Steven nephrosis, 1 with branchio-oto-renal (BOR) syn-
Spielberg Pediatric Research Center, Burns and Allen Research Institute, drome and an absent left kidney and hypoplastic
Cedars-Sinai Medical Center and Department of Pediatrics, University of
California–Los Angeles; and §Department of Plastic and Reconstructive
right kidney).7 A recent study3 of 32 589 consecutive
Surgery, Cedars-Sinai Medical Center, University of California–Los Ange- live births, still births, and abortions over 10 years in
les, Los Angeles, California. the Mainz Congenital Birth Defect Monitoring Sys-
Received for publication Jan 18, 2001; accepted Apr 9, 2001. tem noted a 1.2% prevalence of renal anomalies.
Reprint requests to (J.M.G.) 444 S San Vicente Blvd, Ste 1001, Mark Goodson
Building, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
External ear anomalies of all types, including defor-
PEDIATRICS (ISSN 0031 4005). Copyright © 2001 by the American Acad- mations from fetal constraint, were found in 19.0% of
emy of Pediatrics. all newborns, compared with 23.8% in newborns

http://www.pediatrics.org/cgi/content/full/108/2/e32 PEDIATRICS Vol. 108 No. 2 August 2001 1 of 8


TABLE 1. Percentages of Patients Seen at Cedars-Sinai and Given the wealth of data indicating an association
Dartmouth-Hitchcock Genetics Clinic With Renal Anomalies between ear and renal anomalies, the question is,
Condition n Number With “Should all children with ear anomalies receive renal
Renal Anomalies ultrasonography?” We note that in children with ear
Isolated ear anomaly 9 1 (11%) anomalies, defects within all other organ systems
MCA syndrome 33 11 (33%) occur with a frequency of 5% to 40%.1,2,8 –10 We also
Total 42 12 (28.5%) note that ear and renal anomalies are components of
many multiple congenital anomaly (MCA) syn-
TABLE 2. Percentages of Patients With MCA Syndrome and dromes. We present here data from our own genetics
Renal Anomalies clinic regarding MCA syndrome diagnoses and the
incidence of renal anomalies in patients with ear
MCA Syndrome n Number With
Renal Anomalies anomalies. We then review some of the more signif-
icant MCA syndromes with ear and renal anomalies.
CHARGE association 11 4 (36%)
OAVS 8 0 (0%) METHODS
BOR 7* 2 (29%)
Diabetic embryopathy 3 2 (66%) Charts of patients who had ear anomalies and were seen for
Nager syndrome 3 2 (66%) clinical genetics evaluations at Cedars-Sinai Medical Center and
TBS 2 1 (50%) Dartmouth-Hitchcock Medical Center between 1981 and 2000
were reviewed retrospectively. Only patients who underwent re-
* Several of these patients had been diagnosed previously as hav- nal ultrasound were included in the chart review. Because clinical
ing Goldenhar syndrome because they had ear anomalies and genetics assessments were made by the same clinician at both sites
epibulbar dermoids but were found subsequently to have linkage (J.M.G.), data were combined. The literature regarding MCA syn-
to the locus on 8q for EYA1.11 dromes with ear anomalies was reviewed for epidemiology and
reports of associated renal anomalies.

with renal malformations, showing a slightly signif- RESULTS


icant increased risk (odds ratio: 1.3) for renal anom- A total of 42 patients with ear anomalies received
alies in children with ear anomalies. After patients a renal ultrasound; 12 (29%) of them displayed renal
with syndromic diagnoses were excluded, there con- anomalies. These results are summarized in Table 1.
tinued to be a strong association between auricular Of the 12 patients with renal anomalies, 11 (92%) also
pits or cup ears and specific renal anomalies but no received a diagnosis of MCA syndrome. Percentages
association between auricular tags and renal de- of renal anomalies in patients with an MCA syn-
fects.3 drome are summarized in Table 2.

Fig 1. Top, typical child with CHARGE


association illustrating low-set, posteri-
orly angulated ears with deficient carti-
lage and absent lobules. Note the iris
colobomas and facial asymmetry in this
patient. Bottom, 4 pairs of ears from
children affected with CHARGE associ-
ation demonstrating typical auricular
dysmorphology and asymmetry.

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Fig 2. TBS proband with mild auric-
ular anomaly and hypoplastic thumbs
(also had imperforate anus).

Clinical Syndromes With Associated Renal Anomalies CHARGE association displaying iris colobomas;
CHARGE Association/Syndrome choanal atresia; ear anomalies; and cranial nerve VII,
The majority of patients with CHARGE association IX, and X palsies with semicircular canal, cochlear,
represent sporadic occurrences in an otherwise nor- and temporal bone hypoplasia.12,13
mal family, with several reports supporting the pos- CHARGE association has superficial similarity to
sibility of autosomal dominant transmission. renal-coloboma syndrome, which is caused by mu-
CHARGE association encompasses a wide spectrum tations in the PAX2 gene, and also to DiGeorge se-
of nonrandomly associated malformations, which in- quence, which can be caused by deletion of chromo-
clude coloboma of iris or retina (80%–90%), heart some 22q11, but these genetic abnormalities have
defects (75%– 80%; commonly conotruncal), atresia been eliminated as causes of CHARGE association.14
choanae (50%– 60%), retarded growth (70%) and de-
velopment (100%), genital hypoplasia (70%– 80%),
Townes-Brocks Syndrome
and ear defects (90%).11 Figure 1 shows the triangu-
lar concha, prominent antihelix, and absent lobule Townes-Brocks syndrome (TBS), an autosomal
characteristic of CHARGE ears. Renal anomalies oc- dominant disorder, is caused by a mutation in the
cur in 15% to 25% of patients with CHARGE associ- SALL1 transcription factor gene, which is expressed
ation. Also commonly seen are cleft lip and/or cleft in the developing ear, limb buds, and excretory or-
palate (15%–20%) and tracheoesophageal fistula with gans.15 Like many other autosomal dominant disor-
esophageal atresia (15%–20%).11 ders, phenotypic expression is extremely variable but
Recent reports document increasing evidence for a should include 2 or more of the following: bilateral
syndromic subset of patients within the spectrum of external ear malformation (71%), hand malforma-

Fig 3. A second TBS proband demonstrat-


ing cup ears and hypoplastic thumbs (also
had anteriorly placed anus and renal anom-
aly).

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Fig 4. BOR proband (IV 19) whose initial
diagnosis with familial Goldenhar syn-
drome because of severe micrognathia,
conjunctival dermoids, and microtia. A
branchial cleft cyst is evident on the left side
of his neck, just above his tracheostomy
collar.

tions (56%), and imperforate anus or rectovaginal/ Commonly observed malformations in OAVS in-
rectourethral fistula (47%).16 clude epibulbar dermoids (benign growths on the
Ear defects, seen in Figs 2 and 3, can include mi- medial/lateral aspects of the cornea), preauricular
crotia; overfolded superior helix; “satyr,” “lop,” or tags and pits, microtia with accompanying conduc-
“cup” ear; and preauricular pits or tags; some pub- tive hearing loss, and small jaw resulting in an asym-
lished cases of SALL1 mutations have had ears that metric face.20 Patients with these features in conjunc-
resembled those seen in CHARGE association. Hand tion with cleft lip and/or cleft palate and thoracic
malformations consist mainly of preaxial ray defects, hemivertebrae are termed to have Goldenhar syn-
which can range from polydactyly of a biphalangeal drome, a more severe form of OAVS.
thumb to triphalangeal thumb or thenar hypopla- The epidemiology of OAVS and isolated microtia/
sia.17 Renal malformations have been noted in 27% of anotia (M/A) are similar, with a frequency of ap-
patients with TBS.16 proximately 1.8 per 10 000 births; a male:female ratio
Considerable similarity also exists between TBS of 3:2; and 70% to 90% unilateral involvement, of
and BOR ear anomalies, and this has been empha- which 60% are right sided and 40% are left sided.
sized in the clinical literature,18 along with 1 report of Increasingly, isolated M/A is being considered as the
a 3-generation family with overlapping features of mildest expression of OAVS.20,21
TBS and oculoauriculovertebral spectrum (OAVS) The largest collected population of patients with
with triphalangeal thumbs, preauricular tags, abnor- OAVS was found to have a 5% prevalence (16 of 294)
mal tragus, overfolded superior helices, redundant of genitourinary malformations, but this study in-
anal skin in 2 individuals, micrognathia and macros- cluded renal malformations with genital defects such
tomia in 2 individuals, and epibulbar dermoids in all as hypospadias, hydrocele, chordae penis, cryp-
3 individuals.19 torchidism, and scrotal anomalies.20 Thus, it is un-
known what portion of that 5% was accounted for by
Oculoauriculovertebral Spectrum renal anomalies. Renal anomalies were noted in 4%
OAVS encompasses a broad variety and severity of all cases of M/A.8 –10
of defects in structures derived from the first and
second branchial arches. It is predominantly spo- BOR Syndrome
radic in occurrence, with reports of autosomal dom- BOR syndrome, an autosomal dominant disorder,
inant transmission in only 1% to 2% of cases. is caused by a mutation in the eyeless (EYA1) tran-

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scription factor gene and has a frequency of 1 in ing embryo. This is evidenced by both studies in
40 000 live births. Approximately 60% of cases have animal models and the observation that the risk for
branchial cysts or fistulas, usually found on the ex- fetal malformations increases with elevations in gly-
ternal lower third of the neck, at the median border cosylated hemoglobin.26,27 In addition to macroso-
of the sternocleidomastoid muscle (Fig 4), and 30% to mia, infants who are born to mothers who have
60% of patients with BOR have ear anomalies that either chronic or gestational diabetes are at increased
range from severe microtia to small, lop or cupped risk for dysplastic ears (Fig 7), holoprosencephaly,
ears with overfolded superior helices similar to TBS spine/rib malformations such as caudal dysgenesis,
ears (Fig 5). Preauricular pits are present in 70% to and renal/urinary defects (Martı́nez-Frı́as ML, un-
80% and sometimes can be the only external ear published data).5 Other defects ascribed to IDMs
finding. At least 75% have conductive, sensorineural, include respiratory hypoplasia, cardiovascular de-
or mixed hearing loss, and 12% to 20% have struc- fects, gastrointestinal tract atresia, oculoauriculover-
tural kidney anomalies.22 tebral sequence, and limb reduction.5,28
BOR has extremely variable expression, and even
within the same family, affected individuals show Treacher Collins Syndrome
differing phenotypes (Fig 6). Some members have Treacher Collins syndrome (TCS) is an autosomal
kidney malformations, whereas others may have dominant condition caused by mutations in the trea-
malformations so subtle that imaging cannot identify cle gene, the function of which has not been deter-
them. There are conflicting reports as to whether mined. TCS comprises mostly craniofacial abnormal-
branchio-oto (BO) syndrome is a variant of BOR ities of structures derived from the first branchial
syndrome; some studies of BO families show linkage arch, including downslanting palpebral fissures,
to EYA1,23 whereas others do not.24,25 Two other lower lid colobomas, depressed cheekbones, bilateral
EYA1 homologs have been cloned, and it is possible microtia, conductive hearing loss, micrognathia, cleft
that some cases of BO are caused by mutations in palate, and pharyngeal hypoplasia. Renal anomalies
these other EYA genes or in other genes in the EYA are not recognized as part of this syndrome.29,30
signaling pathways.
Nager Syndrome
Diabetic Embryopathy Nager syndrome is a disorder whose craniofacial
Infants of diabetic mothers (IDMs) have been features are very similar to those of TCS. Mandibular
noted to have malformations in a wide variety of hypoplasia tends to be more severe than that of TCS
organ systems as a result of the direct and indirect and commonly results in respiratory distress; how-
teratogenic effects of hyperglycemia on the develop- ever, limb defects, specifically preaxial anomalies

Fig 5. Ears of affected siblings (top, IV 10 and IV 11; bottom, IV 16 and IV 21) of the BOR proband in Fig 4 again showing marked
variability in ear dysmorphology. Only patient IV 21 had a detectable renal anomaly (single kidney). Note the preauricular pits of IV 11.

http://www.pediatrics.org/cgi/content/full/108/2/e32 5 of 8
Fig 6. Pedigree of family in Fig 5 that
demonstrated linkage to the EYA1 locus
on 8q11 to 13. Note the marked variability
in phenotypic expression.

(hypoplastic or absent thumbs and radii), are the pediatricians to routinely order renal ultrasounds in
principal distinguishing feature. Defects also can be children with virtually any type of ear anomaly.
seen in the lower extremities— hypoplastic halluces Although there are many articles in the literature
and other absent toes. Renal malformations were about this subject, no set of uniform standards exists
found in 7 of 78 (9%) of affected individuals.31–34 The for determining which types of ear anomalies require
mode of inheritance remains unclear; both autosomal renal imaging. Population studies do show an in-
dominant and autosomal recessive inheritance has creased incidence of renal malformations in children
been suggested. with ear anomalies. The Mainz Congenital Birth De-
fect Monitoring System study suggested that minor
Miller Syndrome ear anomalies are extremely common and that pits
Miller syndrome is extremely rare, with only 18 and cup ears are more likely to be associated with
reported cases in the literature. Like Nager syn- renal defects than ear tags in an otherwise normal-
drome, craniofacial features are similar to TCS, but appearing infant.3 This may reflect detection of spo-
lower-lid ectropion is much more pronounced in radic cases of occult BOR. Ear and renal anomalies
Miller syndrome than in the other facial dysostoses. often are components of other MCA syndromes, par-
The cardinal finding of Miller syndrome is ulnar ticularly CHARGE association, TBS, Nager syn-
limb deficiencies such as ulnar hypoplasia and fifth drome, Miller syndrome, and diabetic embryopathy.
finger and/or toe agenesis or underdevelopment. Table 3 summarizes the history and examination
Reflux and hydronephrosis were noted in 1 of the 18 findings found in patients with these syndromes. A
cases (5.5%).35 patient with isolated preauricular pit(s), cup ears, or
an ear anomaly accompanied by positive findings in
DISCUSSION any of these areas should undergo a renal ultrasound
In 1946, Edith Potter’s association of crumpled, to aid in diagnosis of these syndromes. Otherwise, a
flattened ears with bilateral kidney agenesis36 led renal ultrasound is not recommended.

6 of 8 SYNDROMIC EAR ANOMALIES AND RENAL ULTRASOUNDS


Fig 7. Two sporadic cases of lethal diabetic em-
bryopathy with dysplastic ears. Top, case had
vertebral defects and hypoplastic left heart. Bot-
tom, case had rib and vertebral defects, Di-
George sequence, single kidney, and pancreatic
islet cell hyperplasia.

TABLE 3. Areas to Focus on in Initial Evaluation of a Patient TABLE 4. Prevalence of Hearing Loss in Various MCA Syn-
With an External Ear Anomaly dromes and Ear Anomalies
Area Findings Syndrome Percentage With
Hearing Impairment
Birth history Gestational diabetes mellitus (any
class), teratogenic exposures Isolated tag/pit 15–301,2
Family history Ear anomalies, hearing loss CHARGE association 8511
Craniofacial Iris, lid, retinal colobomata; TBS 4416
downslanting palpebral fissures with OAVS 5038
midface hypoplasia; preauricular BOR 7522
pit(s); cup ears; hypoplasia of TCS 5539
semicircular canals and cochlea; Nager syndrome 9531
micrognathia Miller syndrome 1935
Neck Branchial cleft sinuses or cysts
Cardiac Murmurs suggesting congenital heart
defects
Gastrointestinal Imperforate anus, rectovaginal fistula, patients with ear anomalies, which introduces selec-
rectourethral fistula tion bias in that their ears (or other organ systems)
Limbs Abnormal palmar creases, polydactyly, had to be anomalous enough to have been referred
missing 1st or 5th digits, bifurcated/ for a clinical genetics evaluation. Also, patients who
triphalangeal thumbs, thenar
hypoplasia had not undergone renal ultrasonography were ex-
cluded, which would affect our calculated incidence
of renal malformations; however, our numbers agree
Finally, because of the profoundly deleterious ef- with the figures given in review articles of large
fects of delayed diagnosis of hearing impairment on numbers of children with these syndromes and
a child’s communication and social development, thereby provide some guidelines for how to decide
audiologic testing and intervention are crucial in the which children with ear anomalies might benefit
workup of any child with an ear anomaly. A signif- from renal ultrasonography.
icant percentage of children (see Table 4) with ear Ear and kidney development has been character-
anomalies have some degree of hearing loss, and ized in great detail, and we now know that embry-
early detection and referral to an ear, nose, and ologically, ear and kidney primordia arise at differ-
throat specialist for management often are necessary. ent times and develop at different rates. Therefore,
Because the incidence of ear malformations is rel- the association between ear and kidney anomalies
atively rare—almost 1.3 per 10 000 live births—it is usually is not due to an isolated insult to the embryo
difficult for 1 center to conduct a prospective popu- that affects both developing structures at the same
lation study large enough to accumulate sufficient time. Prolonged embryonic insults, such as those
numbers of children with ear anomalies to analyze. seen in IDMs, may cause defects not just in ears and
Our study was limited by review of only our clinic kidneys but also in many other organ systems. This

http://www.pediatrics.org/cgi/content/full/108/2/e32 7 of 8
reflects the ongoing teratogenesis of toxic metabo- proposed as a major criteria for diagnosis of CHARGE syndrome. Am J
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limbs, branchial arches, and somitomeres, all of 458 – 460
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ACKNOWLEDGMENTS
23. Vincent C, Kalatzis V, Abdelhak S, et al. BOR and BO syndromes are
This study received support from SHARE’s Childhood Disabil- allelic defects of EYA1. Eur J Hum Genet. 1997;5:242–246
ity Center, the Steven Spielberg Pediatric Research Center, the 24. Kumar S, Marres HA, Cremers CW, Kimberling WJ. Autosomal domi-
Cedars-Sinai Burns and Allen Research Institute, the Skeletal Dys- nant branchio-otic (BO) syndrome is not allelic to the branchio-oto-renal
plasias NIH/NICHD Program Project Grant (HD22657), and the (BOR) gene at 8q13. Am J Med Genet. 1998;76:395– 401
Medical Genetics NIH/NIGMS Training Program Grant 25. Kumar S, Deffenbacher K, Marres HA, Cremers CW, Kimberling
(GM08243). WJ. Genomewide search and genetic localization of a second gene
We thank Barbara Lawson for her support with this manu- associated with autosomal dominant branchio-oto-renal syndrome:
script. clinical and genetic implications. Am J Hum Genet. 2000;66:1715–1720
26. Reece EA, Homko CJ, Wu YK. Multifactorial basis of the syndrome of
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